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BackgroundIntratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance.MethodsHere, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI treated patients. Deep multi-regional whole exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy.ResultsAngiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts.ConclusionsThese results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC.Trial registrationWe completed a single-arm pilot study at Memorial Sloan Kettering Cancer Center (MSKCC; ClinicalTrials.gov identifier NCT02595918) to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC.

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC., The biobanking of CRC from Hospital Santa Maria, Lisbon, Portugal, was supported by a grant from the Official Portuguese Funding Agency for Science and Technology (FCT: PIC/IC/82821/2007).

Liquid biopsies have the potential to improve early cancer detection, reduce the need for invasive tumor biopsies, and improve personalized oncology treatment. To help drive development within this space, the Blood Profiling Atlas in Cancer (BloodPAC) was created as an initiative born out of the 2016 White House Cancer Moonshot. The BloodPAC seeks to create an open database commons for liquid biopsies with the goal of accelerating the development and approval of safe and effective blood profiling diagnostic technologies for patient benefit. BloodPAC was established as an independent not-for-profit in February 2017 and has made exciting progress in advancing the liquid biopsy landscape. Today, BloodPAC is comprised of over 30 member groups with a diverse range of stakeholders, representing government agencies, academia, pharmaceutical, and diagnostic companies as well as disease specific foundations, payers groups and patient advocates. BloodPAC members actively contribute datasets that include sequencing data from circulating tumor cells, circulating tumor DNA (ctDNA), and exosome assays, alongside relevant clinical data into the BloodPAC Data Commons. The BloodPAC Data Commons helps facilitate the aggregation and harmonization of submitted datasets, allowing researchers to generate study cohorts size to make statistically significant inference in a scalable, reproducible, and secure way. Establishing a comprehensive knowledge base through the BloodPAC Data Commons provides an invaluable reference for anyone entering into the liquid biopsy field, helps develop the evidence required to support clinical utility, assay reproducibility, and provides support for FDA approval and payer reimbursement. This presentation will discuss current progress made within the BloodPAC as an innovative consortium along with the development of the BloodPAC Data Commons, lessons learned, and upcoming next steps. The discussion will focus on examining the BloodPAC consortium's strategy over the past year, the group's work in developing pre- analytical standards, an overview of the contributed data, as well as the collaborative process that has been established with the FDA and CAP to maximize the organization's impact and effectiveness. Citation Format: Jim Godsey. The Blood Profiling Atlas in Cancer: Accelerating progress through collaboration in liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4597.

Circulating tumor cells (CTCs) have been shown in many studies as a possible biomarker for metastasis and may be instrumental for the spread of the disease. Despite advances in CTC capturing technologies, the low frequency of CTCs in cancer patients and the heterogeneity of the CTCs have limited the wide application of the technology in clinic. In this study, we investigated a novel microfluidic technology that uses a size- and deformability-based capture system to characterize CTCs. This unique platform not only allows flex - ibility in the selection of antibody markers but also segregates the CTCs in their own chambers, thus, enabling morphological, immunological and genetic characterization of each CTC at the single cell level. In this study, different breast cancer cell lines including MCF7, MDA-MB-231 and SKBR3, as well as a panel of breast cancer biomarkers were used to test the device. The technology can capture a wide range of cells with high reproducibility. The capturing efficiency of the cells is greater than 80%. In addition, the background of leukocytes is minimized because individual cells are segregated in their own chambers. The device captured both epithelial cancer cells such as MCF7 and SKBR3 and mesenchymal cells such as MDA-MB-231. Immunostaining of the captured cells on the microchannel device suggests that a panel of breast cancer biomarkers can be used to further characterize differential expression of the captured cells.

There is increasing evidence supporting the association of tumor infiltrating lymphocytes (TIL) and drug sensitivity of solid tumors. In particular, primary and meta-analyses have reported a positive correlation between TIL level and outcome in advanced non-small cell lung cancer (NSCLC) treated with checkpoint inhibitors such as PD-1 and PD-L1. Recent trials with immunotherapies have started including TIL assessment in the study protocol in recognition of this metric as a predictive and prognostic biomarker. TIL levels are typically quantified by visual assessment of H&E-stained tumor sections. While this approach is generally accepted as the standard, there is an increased recognition that visual assessment of H&E-stained slides lacks precision and is relatively subjective (Salgado R, 2015; Schalper KA, 2015). Furthermore, as investigators are often also interested in measurements of additional biomarkers such as IFNg as well as the drug targets, a gene panel approach offers a convenient solution to objectively quantify expression levels of these informative markers. Here we report the discovery and verification of a unique gene expression signature that is capable of stratifying FFPE samples of NSCLC tumors by TIL levels and histopathology phenotypes (adenocarcinoma vs. squamous cell carcinoma). Gene expression was measured by an RNA Ion AmpliSeq Gene Expression research panel* containing 200 assays. Each research sample was measured with replicates at library generation step and sequencing step. Technical replicates were found to have >0.99 correlation among each other. Assays on the panels were also found to be robust with respect to low input amount (1-10 ng RNA). *For Research Use Only. Not for use in diagnostic procedures. Citation Format: Ann Mongan, Sophie Rozenzhak, Geoffrey Bien, David Chi, Hiroyoshi Nishikawa, Fiona Hyland, Jim Godsey. Novel biomarkers and multiplexed NGS to stratify FFPE NSCLC by tumor infiltrating lymphocytes and histopathology phenotypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3941.